Gabantin 300 capsules 300 mg blister No. 30

Instructions Gabantin 300 capsules 300 mg blister No. 30

Composition

active ingredient: gabapentin;

1 capsule contains 300 mg of gabapentin calculated as 100% anhydrous substance;

excipients: microcrystalline cellulose, corn starch, talc;

capsule composition: gelatin, titanium dioxide (E 171).

Dosage form

Capsules.

Main physical and chemical properties: hard gelatin capsules of white color. The contents of the capsules are white or almost white powder; the presence of compressed columns or lumps that disintegrate when pressed is allowed.

Pharmacotherapeutic group

Antiepileptic drugs. ATX code N03A X12.

Pharmacological properties

Pharmacodynamics

Mechanism of action

Gabapentin is known to readily penetrate the brain and prevent seizures in a number of animal studies modeling epilepsy.

Gabapentin does not alter GABA (gamma-aminobutyric acid) metabolism and has no affinity for GABA A or GABA B receptors. It does not bind to other neurotransmitter receptors in the brain and does not interact with sodium channels. Gabapentin binds with high affinity to the α2-δ (alpha2-delta) subunit of voltage-gated calcium channels, which is thought to be responsible for its anticonvulsant effects in animals. A wide range of screening studies have not shown that gabapentin binds to targets other than α2-δ.

Several preclinical studies suggest that the pharmacological activity of gabapentin may be mediated by binding to the α2-δ subunit through decreased release of excitatory neurotransmitters in various parts of the central nervous system (CNS). This activity may underlie the anticonvulsant effects of gabapentin, but its role in achieving this effect in humans has not yet been studied.

Gabapentin has also been shown to be effective in a number of preclinical animal studies modeling pain. It is believed that the specific binding of gabapentin to the α2-δ subunit causes several different effects that could provide analgesic effects in animal pain models. Gabapentin may exert analgesic effects at both the spinal cord and higher brain centers by interacting with descending inhibitory pathways of pain sensitivity. The role of these properties in the clinical efficacy of the drug in humans has not been studied.

Clinical efficacy and safety

Clinical trials of adjunctive therapy for partial onset seizures in children aged 3 to 12 years have shown a numerically greater but not statistically significant difference in the 50% response rate in favor of gabapentin compared with placebo. Additional post-hoc analyses of responder rates by age showed no significant effect of age using either continuous or binary variables (age groups 3-5 years and 6-12 years). The results of this analysis are presented in Table 1.

Table 1

Response rate (≥50% improvement) by treatment category and group. MITT population*

* The MITT (modified population of patients who took at least one dose of a drug) includes all patients randomized to the study who were able to complete seizure diaries to a sufficient degree for assessment for 28 days during the baseline and double-blind phases.

Pharmacokinetics

Absorption

When taken orally, gabapentin is rapidly absorbed from the digestive tract regardless of food intake. The time to reach maximum concentration is 2-3 hours. There is a tendency for the bioavailability of gabapentin (the absorbed part of the drug) to decrease with increasing dose. The absolute bioavailability of gabapentin when taking 300 mg capsules is approximately 60%. Food intake, including fatty foods, does not have a clinically significant effect on the pharmacokinetics of gabapentin. Pharmacokinetics do not change with repeated administration. Although the plasma concentration of the drug in clinical studies varied from 2 to 20 μg/ml, this value did not determine the efficacy and safety of the drug.

Pharmacokinetic parameters are listed in Table 2.

Table 2

Summary of mean (%CV) steady-state pharmacokinetic parameters after administration of the drug every 8 hours

Cmax = maximum steady-state plasma concentration;

tmax = time to reach Cmax;

AUC (0-8) = steady-state area under the pharmacokinetic concentration-time curve from time 0 to 8 hours after drug administration;

Ae% = percentage of dose excreted unchanged in urine from time 0 to 8 hours after drug administration;

ND = not available.

Distribution

Gabapentin does not bind to plasma proteins, the volume of distribution is 57.7 liters. It crosses the blood-brain barrier: in patients with epilepsy, the concentration of gabapentin in the cerebrospinal fluid is approximately 20% of the corresponding equilibrium concentration of the drug in blood plasma. It penetrates into breast milk.

Biotransformation

Gabapentin is almost not metabolized in the human body, does not induce or inhibit liver enzymes. The drug does not interfere with the metabolism of antiepileptic drugs used in general practice.

Breeding

Excreted by the kidneys unchanged. T1/2 is dose-independent and averages 5-7 hours in patients with normal renal function. Removed from the blood by hemodialysis. In elderly patients and patients with impaired renal function, plasma clearance of gabapentin is reduced. The elimination rate constant, plasma clearance, and renal clearance are directly proportional to the level of creatinine clearance.

Dose adjustment is recommended for patients with renal impairment and patients on hemodialysis.

It is known that the pharmacokinetics of gabapentin in children were evaluated in 50 healthy volunteers aged 1 month to 12 years. In general, when calculating the dose per kilogram of body weight (mg/kg), plasma concentrations of gabapentin in children aged 5 years and older did not differ from those in adults.

A pharmacokinetic study in 24 healthy children aged 1 to 48 months showed approximately 30% lower area under the concentration-time curve (AUC), lower Cmax and higher clearance per unit body weight compared to data obtained in children aged 5 years and older.

Linearity/nonlinearity

The bioavailability of gabapentin (the absorbed portion of the drug) decreases with increasing dose, which indicates the nonlinearity of the pharmacokinetics of the drug, namely the bioavailability parameters (F): Ae%, CL/F, Vd/F. Elimination pharmacokinetics (pharmacokinetic parameters that do not include F, such as CLr and T1/2) have a linear pattern. The equilibrium plasma concentration of gabapentin is predictable based on data from a single dose of the drug.

Indication

Epilepsy

As monotherapy in the treatment of partial seizures with or without secondary generalization in adults and children aged 12 years and older.

As adjunctive therapy in the treatment of partial seizures with or without secondary generalization in adults and children aged 6 years and older.

Treatment of peripheral neurological pain in postherpetic neuralgia or diabetic neuralgia in adults.

Contraindication

Hypersensitivity to any components of the drug.

Interaction with other medicinal products and other types of interactions

Cases of respiratory depression and/or sedation associated with the concomitant use of gabapentin and opioids have been described. In some reports, the authors express particular concern about the use of the combination of gabapentin and opioids, especially in elderly patients.

When 60 mg of morphine controlled-release capsules were administered 2 hours before 600 mg of gabapentin capsules, the mean AUC of gabapentin increased by 44% compared to the AUC of gabapentin administered without morphine. Therefore, the patient should be closely monitored for signs of CNS depression, such as drowsiness, and the dose of morphine or gabapentin should be reduced appropriately.

No cases of interaction of gabapentin with phenobarbital, phenytoin, valproic acid or carbamazepine have been observed. Simultaneous use with other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital) is possible; drugs that block tubular secretion and reduce the renal excretion of gabapentin.

The pharmacokinetics of gabapentin are similar in healthy subjects and in patients with epilepsy who took these antiepileptic drugs.

Since gabapentin is almost not bound to serum proteins, is not metabolized, does not induce oxidative liver enzymes, the likelihood of its interaction with other drugs is very low. Simultaneous use of gabapentin and oral contraceptives containing norethisterone and/or ethinyl estradiol does not affect the equilibrium concentration of these drugs. When used simultaneously with antacids containing aluminum and magnesium, the bioavailability of gabapentin decreases by approximately 20%, in this regard, it is recommended to take the drug no earlier than 2 hours after taking antacids. Myelotoxic drugs increase hematotoxicity (leukopenia). Probenecid does not affect the excretion of gabapentin by the kidneys. When used together with cimetidine, the renal excretion of gabapentin is slightly reduced, but this is not clinically significant.

Application features

Severe, life-threatening systemic hypersensitivity reactions, such as drug rash with eosinophilia and systemic symptoms (DRESS), have been reported in patients taking medicinal products including gabapentin (see section 4.8). It is important to note that early signs of hypersensitivity, such as fever or lymphadenopathy, may occur before the rash appears. If such symptoms occur, gabapentin should be discontinued immediately unless an alternative cause for the symptoms has been identified.

Anaphylaxis

Gabapentin may cause anaphylaxis. The following symptoms have been reported: difficulty breathing, swelling of the lips, throat and tongue, and hypotension, requiring emergency treatment. Patients should be instructed to discontinue gabapentin immediately and seek emergency medical attention if anaphylaxis occurs (see section 4.8).

Suicidal thoughts and behavior

Suicidal ideation and behavior have been reported in patients treated with antiepileptic drugs for several indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal ideation and behavior, the mechanism of which is unknown, but the available data do not exclude the possibility of an effect of gabapentin. Patients taking antiepileptic drugs should be closely monitored for signs of suicidal ideation and behavior and treated as necessary. The mechanism of this risk is unknown, and the available data do not exclude an increased risk with gabapentin. Patients (and caregivers of patients) should be advised to seek medical advice if signs of suicidal ideation and behavior develop.

Acute pancreatitis

If acute pancreatitis occurs while taking gabapentin, discontinuation of gabapentin is indicated.

Convulsive seizures

Although there is no evidence of reversible seizures, abrupt discontinuation of anticonvulsant medications may precipitate status epilepticus.

As with other anticonvulsants, some patients may experience an increase in seizure frequency or the development of new seizure types while taking gabapentin. Attempts to withdraw concomitant antiepileptic therapy in treatment-resistant patients receiving more than one antiepileptic drug in order to switch to gabapentin monotherapy are rarely successful.

The drug is ineffective in treating primary generalized seizures, such as absences, and may even worsen them in some patients. Therefore, gabapentin should be prescribed with caution in patients with mixed seizures, including absences.

Dizziness, drowsiness, loss of consciousness and impaired mental activity

Gabapentin treatment has been associated with dizziness and drowsiness, which may lead to accidental injury (due to falls). Based on post-marketing data, cases of confusion, loss of consciousness and mental impairment have been reported. Therefore, patients should be advised to exercise caution until they are fully aware of the potential effects of the drug.

Concomitant use with opioids

In patients requiring additional opioid therapy, increased gabapentin concentrations may occur. Therefore, patients should be monitored for signs of CNS depression such as drowsiness, sedation, and respiratory depression. The dose of gabapentin or opioids should be reduced accordingly (see Interactions).

Respiratory depression

Gabapentin has been associated with severe respiratory depression. Patients with impaired respiratory function, respiratory and nervous system diseases, renal failure, concomitant use of CNS depressants, and elderly patients are at increased risk of severe respiratory depression. These patients may require dose adjustment.

Elderly patients (65 years and older)

There have been no systematic studies of gabapentin in patients over 65 years of age. In one double-blind study in patients with neuropathic pain, somnolence, peripheral edema, and asthenia were reported to be slightly more common in patients over 65 years of age than in younger patients. Apart from these findings, no differences in the adverse event profile were observed in this group compared to younger patients in clinical trials.

Children

The effects of long-term (>36 weeks) gabapentin treatment on learning ability, intelligence, and development in children and adolescents have not been adequately studied. Therefore, the benefits of prolonged therapy should be carefully weighed against the potential risks of such treatment.

Abuse and addiction

Dose reduction, discontinuation of the drug or replacement with another (alternative) should be carried out gradually, over at least 1 week. Abrupt discontinuation of antiepileptic therapy in patients with epilepsy may provoke an increase in the frequency of seizures (status epilepticus). Caution is recommended when treating patients with a history of psychotic illness. The use of alcohol and narcotic drugs may increase CNS side effects, such as confusion and ataxia.

Laboratory tests

When performing semi-quantitative determination of total protein in urine using rapid tests, false positive results may be obtained. Therefore, if necessary, it is recommended to perform additional analyses using other methods (biuret method, turbidimetric method, dye tests), or these methods should be used at the very beginning.

Ability to influence reaction speed when driving vehicles or other mechanisms

Gabapentin may have minor or moderate influence on the ability to drive or use machines. Gabapentin acts on the central nervous system and may cause drowsiness, dizziness and other similar symptoms. Even in the case of mild or moderate severity, these undesirable effects may be potentially dangerous for patients who drive or perform other potentially hazardous work that requires special attention and speed of psychomotor reactions. This is especially true at the beginning of treatment and after increasing the dose.

Use during pregnancy or breastfeeding

Pregnancy period

Risks associated with epilepsy and all anticonvulsant drugs

The risk of birth defects in children born to mothers who have received anticonvulsants increases by 2-3 times. The most frequently reported cases are cleft lip, cardiovascular defects, and neural tube defects. Multiple antiepileptic therapy is associated with a higher risk of congenital malformations, so it is important to use monotherapy whenever possible. Women planning pregnancy and women of childbearing age should be instructed that anticonvulsant therapy should be reviewed in the event of a planned pregnancy. Anticonvulsant therapy should not be stopped abruptly, as this may provoke seizures, which can seriously harm both the mother and the fetus. Developmental delay in children whose mothers had epilepsy is rare. It is impossible to determine exactly how developmental delay in a child can be caused - by genetic, social factors, maternal illness, or anticonvulsant therapy.

Risks associated with gabapentin therapy

Gabapentin crosses the placenta. There are no adequate data from the use of gabapentin in pregnant women. Animal studies have been reported to show reproductive toxicity. The potential risk to humans is unknown. Gabapentin should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the fetus. It is not known whether gabapentin is associated with an increased risk of birth defects when used during pregnancy, as epilepsy itself and the use of antiepileptic drugs may cause such defects during this period.

Breastfeeding period

Gabapentin is excreted in human milk. Since the effects on breast-fed infants are unknown, caution should be exercised when gabapentin is administered to lactating women. Therefore, breast-feeding should be discontinued during treatment with gabapentin.

Fertility

No effects on fertility were observed in animal studies.

Method of administration and doses

For oral use.

Gabapentin can be taken regardless of food intake; the capsules should be swallowed whole with sufficient water (e.g. 1 glass of water).

For all indications, the recommended dose titration schedule at the very beginning of treatment for adults and children aged 12 years and older is shown in Table 3.

Table 3

Dosage instructions for children under 12 years of age are provided in this section below.

Discontinuation of gabapentin therapy

If gabapentin treatment needs to be discontinued, this should be done gradually, over at least 1 week, regardless of the indication.

Epilepsy

Patients with epilepsy require long-term therapy. The dosage is determined according to individual tolerability and effectiveness of the drug.

Adults and children aged 12 and over

The effective dose of Gabantin is 900-3600 mg per day (divided into 3 doses).

Subsequently, depending on the individual patient's response to treatment and tolerability of the drug, the dose can be gradually increased by 300 mg per day every 2-3 days to a maximum dose of 3600 mg per day. Some patients may require a slower titration of the gabapentin dose. The minimum period to reach a dose of 1800 mg per day corresponds to one week, a dose of 2400 mg per day - 2 weeks, a dose of 3600 mg per day - a total of 3 weeks. There is evidence that a dose of up to 4800 mg per day was well tolerated in long-term studies. The daily dose should be divided into 3 doses. The maximum interval between doses of the drug should not exceed 12 hours to prevent the development of seizures.

Children aged 6 and over

Treatment should be initiated at a dose of 10-15 mg/kg/day. The effective dose for children aged 6 years and older is 25-35 mg/kg/day, achieved by titration over approximately 3 days.

There is evidence that a dose of 50 mg/kg body weight per day was well tolerated in long-term studies. The daily dose is divided into 3 doses, the maximum interval between doses of the drug should not exceed 12 hours.

There is no need to monitor plasma concentrations. Gabapentin can subsequently be used in combination with other antiepileptic drugs without regard to changes in gabapentin plasma concentrations or serum concentrations of other antiepileptic drugs.

Peripheral neuropathic pain in adults

Treatment can be initiated either by titrating the dose as described in Table 3 or by prescribing an initial dose of 900 mg per day, divided into three doses. Subsequently, depending on the individual patient's response to treatment and tolerability, the dose can be gradually increased by 300 mg per day every 2-3 days to a maximum dose of 3600 mg per day. Some patients may require a slower titration of gabapentin. The minimum period to reach a dose of 1800 mg per day corresponds to one week, a dose of 2400 mg per day - 2 weeks, a dose of 3600 mg per day - a total of 3 weeks.

In the treatment of peripheral neuropathic pain, particularly painful diabetic neuropathy and postherpetic neuralgia, efficacy and safety have not been studied for treatment periods longer than 5 months.

If it is necessary to use gabapentin in the treatment of peripheral neuropathic pain for more than 5 months, the doctor should evaluate the patient's clinical condition and determine the need for additional treatment.

Instructions regarding prescriptions for all indications

For patients with a weakened general condition of the body, with low body weight, after organ transplantation, the dose of gabapentin should be titrated more slowly by using a dosage form with a lower dosage of the drug or increasing the interval between dose increases.

Elderly patients (aged 65 years and over)

Elderly patients may require dosage adjustment due to age-related decline in renal function (see Table 4).

Elderly patients may commonly experience drowsiness, peripheral edema, and asthenia.

Patients with renal impairment

In patients with renal impairment or those on hemodialysis, dose adjustments are recommended as described in Table 4.

Table 4

Gabapentin doses in adults based on renal function

a The total daily dose should be divided into 3 doses. A reduced dosage should be used in patients with renal impairment (creatinine clearance < 79 mL/min).

b Administer at a dose of 300 mg every other day.

c In patients with creatinine clearance < 15 mL/min, the daily dose should be reduced proportionally to the creatinine clearance (e.g., a creatinine clearance of 7.5 mL/min should be half the daily dose used in patients with a creatinine clearance of 15 mL/min).

Patients on hemodialysis

For anuric patients on hemodialysis who have never received gabapentin before, a loading dose of 300 to 400 mg is recommended, followed by 200 to 300 mg of gabapentin after each 4-hour hemodialysis session. Gabapentin should not be taken on non-dialysis days.

For patients with renal impairment undergoing hemodialysis, a maintenance dose of gabapentin should be administered according to the recommendations in Table 4. In addition to the maintenance dose, it is recommended to administer 200-300 mg of the drug after each 4-hour hemodialysis session.

Children

Gabapentin is indicated as adjunctive therapy in the treatment of partial seizures with or without secondary generalization in children aged 6 years and older.

Gabapentin is indicated as monotherapy in the treatment of partial seizures with or without secondary generalization in children aged 12 years and older.

Overdose

Reduced absorption of gabapentin at high doses may limit the absorption of the drug in overdose, and therefore minimize its toxicity in overdose.

Overdose of gabapentin in combination with CNS depressants may lead to coma.

Treatment: symptomatic therapy.

Depending on the clinical picture, hemodialysis may be performed, although experience shows that this is not necessary.

Hemodialysis may be indicated for patients with severe renal failure.

It is known that in studies with oral administration of gabapentin at a dose of 8 g/kg, a lethal dose was not established. Signs of acute toxicity such as ataxia, difficulty breathing, ptosis, decreased activity or agitation were reported.

Adverse reactions

Adverse reactions are classified according to frequency: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency unknown (frequency cannot be estimated from the available data). Adverse reactions that occurred in different studies with different frequencies are presented in the group with the highest frequency that occurred. Additional adverse reactions reported in post-marketing studies are listed in the category "frequency unknown" (cannot be estimated from the available data) and are highlighted in italics. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations: very common – viral infections; common – pneumonia, respiratory infections, urinary tract infections, otitis media.

Blood and lymphatic system disorders: often – leukopenia; frequency unknown – thrombocytopenia.

Immune system disorders: uncommon - allergic reactions (e.g. urticaria); frequency unknown - hypersensitivity syndrome (systemic reaction with various manifestations, namely fever, rash, hepatitis, lymphadenopathy, eosinophilia and, sometimes, other signs and symptoms), anaphylaxis (see section "Special warnings and precautions for use").

Metabolism: often - anorexia, increased appetite; infrequently - hyperglycemia (most often in patients with diabetes mellitus); rarely - hypoglycemia (most often in patients with diabetes mellitus); frequency unknown - hyponatremia.

On the part of the psyche: often - hostility, confusion, emotional lability, depression, anxiety, increased nervous excitability, thinking disorders; infrequently - agitation; frequency unknown - hallucinations.

Nervous system: very often - drowsiness, dizziness, ataxia; often - convulsions, hyperkinesia, dysarthria, amnesia, tremor, insomnia, headache, paresthesia, hypoesthesia, coordination disorders, nystagmus, increased, decreased or absent reflexes; infrequently - hypokinesia, mental disorders; rarely - loss of consciousness; frequency unknown - other movement disorders (e.g., choreoathetosis, dyskinesia, dystonia).

On the part of the organs of vision: often - diplopia, amblyopia.

On the part of the auditory organs: often - vertigo; frequency unknown - tinnitus.

Cardiac: infrequently - palpitations.

Vascular disorders: often - arterial hypertension, vasodilation.

From the respiratory system, chest organs and mediastinum: often - rhinitis, pharyngitis, shortness of breath, bronchitis, cough; rarely - respiratory depression.

Gastrointestinal: often - nausea, vomiting, abdominal pain, gingivitis, constipation or diarrhea, dry mouth or throat, dyspeptic phenomena, dental changes, flatulence; infrequently - dysphagia; frequency unknown - pancreatitis.

From the hepatobiliary system: frequency unknown - hepatitis, jaundice.

Skin and subcutaneous tissue disorders: common: facial edema, purpura, most often described as bruising resulting from physical trauma, skin rash, pruritus, acne; frequency unknown: erythema multiforme exudative, Stevens-Johnson syndrome, angioedema, alopecia, drug rash with eosinophilia and systemic symptoms (see section "Special warnings and precautions for use").

Musculoskeletal and connective tissue disorders: often - myalgia, arthralgia, back pain, muscle twitching; frequency unknown - myoclonus, rhabdomyolysis.

Renal and urinary disorders: frequency unknown - acute renal failure, urinary incontinence.

From the reproductive system: often - impotence; frequency unknown - breast hypertrophy, gynecomastia, sexual dysfunction (including changes in libido, ejaculation disorders and anorgasmia).

General disorders: very common - fatigue, fever; common - peripheral edema, gait disturbance, asthenia, pain, malaise, flu-like syndrome; uncommon - generalized edema; frequency unknown - withdrawal reactions (restlessness, insomnia, pain, nausea, increased sweating), chest pain. Sudden death has been reported, although a causal relationship to gabapentin treatment has not been established.

Investigations: common – decreased white blood cell count, weight gain; uncommon – increased liver function tests (AST, ALT and bilirubin); frequency unknown – increased blood creatine phosphokinase.

Injuries, poisoning, and complications of manipulations: often - accidental injuries, fractures, scratches; infrequently - falls.

Myopathy with elevated creatinine levels has been reported in patients on hemodialysis with end-stage renal disease.

There is evidence that respiratory infections, middle ear infections, bronchitis, and seizures were observed only in children, and the occurrence of aggressive behavior and hyperkinesias in children was also frequently reported.

Expiration date

3 years.

Storage conditions

Store out of the reach of children, in the original packaging at a temperature not exceeding 25 ºС.

Packaging

10 capsules in a blister; 3 blisters in a cardboard pack.

Vacation category

According to the recipe.

Producer

"Pharma Start" LLC.

Location of the manufacturer and its business address

Ukraine, 03124, Kyiv, V. Havela Blvd., 8.